The goals of this project include the definition of the stereochemistry of thiamine pyrophosphate (cocarboxylase), the determination of its valence structure and the elucidation of how the valence charge densities reflect changes in the molecular charge, conformation and crystalline environment. The structures of thiamine, its C2 adducts, which are reaction intermediates, and its metabolic antagonists will be determined in a variety of crystalline environments using X-ray diffraction data. The charge distribution within these molecules will be examined by the L-shell projection method. Knowing the charge density distribution in these various thiamine structures will show whether there is stereoelectronic coupling between the aromatic rings of thiamine and if so, how it is effected by changes within the molecule and the environment of the molecule. This knowledge should provide a clue as to why the F form of thiamine is so highly favored and should indicate the mechanistic role of the pyrimidine ring by showing how it influences the active site at C2 electronically. Morever, the electronic and molecular structure of TPP should form a logical framework for resolving differences in the interpretation of its molecular properties as obtained by various experimental and theoretical procedures. In this way, the proposed research should contribute significantly toward a better understanding of the catalytic role of thiamine, which is an essential cofactor in many crucial enzyme systems.